Unveiling the role of network and systems biology in drug discovery

Pujol, Albert; Mosca, Roberto; Farrés, Judith; Aloy, Patrick

doi:10.1016/j.tips.2009.11.006

Cited by 315 publications

(204 citation statements)

References 94 publications

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“…The results of this second set of enrichment analyses, where we deal with missing and dubious interactions, are very consistent with what we observed in complete interactome networks, showing a clear depletion in the conservation of disordered interactions. In addition, they also support the notion that, even if incomplete and error prone, current versions of interactomes already contain enough quality information to permit the analysis of their global and emerging properties (42).…”

Section: Fig 3 Conservation Of Disordered Interactions In Interactomentioning

confidence: 54%

The Role of Structural Disorder in the Rewiring of Protein Interactions through Evolution

Mosca

Pache

Aloy

2012

Molecular & Cellular Proteomics

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Structurally disordered regions play a key role in proteinprotein interaction networks and the evolution of highly connected proteins, enabling the molecular mechanisms for multiple binding. However, the role of protein disorder in the evolution of interaction networks has only been investigated through the analysis of individual proteins, making it impossible to distinguish its specific impact in the (re)shaping of their interaction environments. Now, the availability of large interactomes for several model organisms permits exploration of the role of disorder in protein interaction networks not only at the level of the interacting proteins but of the interactions themselves. By comparing the interactomes of human, fly, and yeast, we discovered that, despite being much more abundant, disordered interactions are significantly less conserved than their ordered counterparts. Furthermore, our analyses provide evidence that this happens not only because disordered proteins are less conserved but also because they display a higher capacity to rewire their interaction neighborhood through evolution. Overall, our results support the hypothesis that conservation of disorder gives a clear evolutionary advantage, facilitating the change of interaction partners during evolution. Moreover, this mechanism is not exclusive of a few anecdotal cases but a global feature present in the interactome networks of entire organisms.

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Section: Fig 3 Conservation Of Disordered Interactions In Interactomentioning

confidence: 54%

The Role of Structural Disorder in the Rewiring of Protein Interactions through Evolution

Mosca

Pache

Aloy

2012

Molecular & Cellular Proteomics

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“…Recent studies have shown that causative/susceptibility genes for many disease phenotypes often work together within the same biological module (Oti and Brunner 2007), be it a protein complex, a pathway, or a protein interaction sub-network, highlighting a strong link between protein connectivity and disease (Zanzoni et al 2009;Pujol et al 2010). Indeed, the number of interactions observed between disease-causing genes in several pathologies is often much higher than what would be expected by chance, and the discovery of unexpected relationships between apparently unrelated genes has emerged as a powerful tool for the identification of novel genes involved in complex diseases such as breast cancer (Pujana et al 2007), Huntington (Goehler et al 2004), schizophrenia (Camargo et al 2007), or cerebral ataxias (Lim et al 2006).…”

mentioning

confidence: 99%

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Soler-López¹,

Zanzoni²,

Lluís³

et al. 2010

Genome Res.

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109

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Recent advances toward the characterization of Alzheimer's disease (AD) have permitted the identification of a dozen of genetic risk factors, although many more remain undiscovered. In parallel, works in the field of network biology have shown a strong link between protein connectivity and disease. In this manuscript, we demonstrate that AD-related genes are indeed highly interconnected and, based on this observation, we set up an interaction discovery strategy to unveil novel AD causative and susceptibility genes. In total, we report 200 high-confidence protein-protein interactions between eight confirmed AD-related genes and 66 candidates. Of these, 31 are located in chromosomal regions containing susceptibility loci related to the etiology of late-onset AD, and 17 show dysregulated expression patterns in AD patients, which makes them very good candidates for further functional studies. Interestingly, we also identified four novel direct interactions among well-characterized AD causative/susceptibility genes (i.e., APP, A2M, APOE, PSEN1, and PSEN2), which support the suggested link between plaque formation and inflammatory processes and provide insights into the intracellular regulation of APP cleavage. Finally, we contextualize the discovered relationships, integrating them with all the interaction data reported in the literature, building the most complete interactome associated to AD. This general view facilitates the analyses of global properties of the network, such as its functional modularity, and triggers many hypotheses on the molecular mechanisms implicated in AD. For instance, our analyses suggest a putative role for PDCD4 as a neuronal death regulator and ECSIT as a molecular link between oxidative stress, inflammation, and mitochondrial dysfunction in AD.

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“…In addition, interaction networks have become essential and powerful tools for associating proteins with distinct phenotypes and diseases (34,35), as well as for studying pharmacological drug-target relationships (36,37).…”

Section: Protein Interactions and Networkmentioning

confidence: 99%

“…As many drugs have multiple targets and targets are modulated by several drugs, an alternative, efficient approach toward therapeutic treatment is the systematic re-use of drugs with established safety and pharmacokinetic profiles. This approach is believed to reduce risks and costs in drug development while improving its efficiency (37). In fact, newly identified indications can be validated starting from Phase II clinical trials, which typically last two years and cost $17 million (71).…”

Section: Drug Repositioningmentioning

confidence: 99%

“…IGF-1R inhibitors, on the other hand, inhibit the crosstalk between HER2 and IGF receptors which, in turn, impacts the activation of alternative pathways that are implicated in trastuzumab resistance. These examples indicate that synergistic drug combinations either target the same or different proteins from the same or related pathways as well as from cross-talking routes, which requires a thorough understanding of diseaserelated pathways (37). Extensive investigations of pathways involved in metastatic breast cancer identified four breast cancer genes, namely EGFR, MMP-1, and MMP-2, which induce the spread of tumor cells throughout the circulatory system into lung parenchyma (82).…”

Section: Drug Combinationsmentioning

confidence: 99%

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From protein interaction networks to novel therapeutic strategies

Jaeger

Aloy

2012

IUBMB Life

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SummaryCellular mechanisms that sustain health or contribute to disease emerge mostly from the complex interplay among various molecular entities. To understand the underlying relationships between genotype, environment and phenotype, one has to consider the intricate and nonsequential interaction patterns formed between the different sets of cellular players. Biological networks capture a variety of molecular interactions and thus provide an excellent opportunity to consider physiological characteristics of individual molecules within their cellular context. In particular, the concept of network biology and its applications contributed largely to recent advances in biomedical research. In this review, we show (i) how biological networks, i.e., protein-protein interaction networks, facilitate the understanding of pathogenic mechanisms that trigger the onset and progression of diseases and (ii) how this knowledge can be translated into effective diagnostic and therapeutic strategies. In particular, we focus on the impact of network pharmacological concepts that go beyond the classical view on individual drugs and targets aiming for combinational therapies with improved clinical efficacy and reduced safety risks.2012 IUBMB IUBMB Life, 64(6): 529-537, 2012

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Unveiling the role of network and systems biology in drug discovery

Cited by 315 publications

References 94 publications

The Role of Structural Disorder in the Rewiring of Protein Interactions through Evolution

The Role of Structural Disorder in the Rewiring of Protein Interactions through Evolution

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

From protein interaction networks to novel therapeutic strategies

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